Gangliosides are specialized sialic acid-containing glycolipids abundant in the outer region of the neuronal lipid bilayer and intestinal brush border. The intestine contains a relatively high amount of ganglioside (as much as 7% of total lipids (Christiansen et al, 1981; Forstner et al., 1973). Change occurs in the composition and molecular structure of gangliosides during intestinal development (Bouhours et al., 1983; Glickman et al, 1976). Total intestinal lipids are comprised of 25 to 35% sphingolipids, including gangliosides and sphingomyelin (Christiansen et al, 1981; Forstner et al., 1973), and microvillus membranes are more enriched in gangliosides than the plasma membranes (Forstner et al., 1973).
Gangliosides are located at the surface of the cell membrane with the hydrophilic oligosaccharide chain extending into the extracellular space. Glycosphingolipid constitutes approximately 20% of the brush border membrane lipids (Forstner et al., 1973). The dominant ganglioside is GM3 which is 7 times more concentrated in the neonatal compared to adult intestine of rats (Bouhours et al., 1983). The specific physiological roles of gangliosides are poorly understood, however, studies showed that gangliosides provide binding sites for a wide range of pathogens including viruses, bacteria and fungi (Holmgren et al., 1985; Kyogashima et al., 1989; Laegreid and Otnaess, 1987; and Rolsma et al., 1998). For example, ganglioside GM3 acts as a natural receptor in pig small intestine for rotavirus (Rolsma et al., 1998) and the enterotoxigenic bacteria Escherichia coli (E. coli) K99 (Kyogashima et al., 1989). Ganglioside GM1 in human intestine (Holmgren et al., 1985) and in human milk (Laegreid et al., 1987) also provides receptors for enterotoxin of Vibrio cholerae and the heat-labile E. coli, thereby acting as a physiological barrier for protection against these enteric infections.
Previous studies showed that gangliosides exist in clusters in the plasma membrane forming glycosphingolipid enriched domains and that these domains are the preferential interaction sites between target cells and pathogens (Karlsson, 1995). Preterm newborn infants fed ganglioside supplemented formula at a concentration of 1.43 mg/100 Kcal, were shown to have significantly lower numbers of E. coli and bifidobacteria in the feces (Rueda et al., 1998).
During early development, important morphological changes occur in the total and relative amounts of gangliosides in neuronal tissues of the brain and retina (Asou et al., 1989; Baumann et al., 1976; Daniotti et al., 1994). One of the primary roles of gangliosides is activation of neuronal cell differentiation and proliferation (Ledeen et al., 1998), influencing synaptogenesis and neuritogenesis (Byrne et al., 1983; Svennerholm et al., 1989) and offering protection against neuronal injury (Guelman et al., 2000; Mohand-Said et al., 1997). Functions in the intestinal mucosa involve toxin receptors of bacterial and viruses (Thompson et al., 1998; Rolsma et al., 1998) and immune activators (Vazquez et al., 2001). Radiolabeling studies have shown that exogenous gangliosides and sphingomyelin are hydrolyzed by enterocyte membrane-bound enzymes such as sphingomyelinase and/or ceramidase (Merrill et al., 1997; Schmelz et al., 1994; Nilsson, 1968). Metabolites such as ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate are transported into enterocytes and reutilized in synthesis of gangliosides or sphingomyelin or both (Merrill et al., 1997; Schmelz et al., 1994). Since gangliosides and sphingomyelin are incorporated into lipoproteins and chylomicrons (Hara et al., 1987; Merrill et al., 1995), dietary gangliosides, sphingomyelin and/or their intestinal metabolites are likely to be transported throughout the body to affect sphingolipid biosynthesis in other organs (Vesper et al., 1999). Studies have suggested a possible interaction between sphingolipids and phospholipids (Merrill et al., 1997; Schmelz et al., 1994; Ogura et al., 1988). Sphingosine-1-phosphate is metabolized into ethanolamine phosphate and hexadecanal, both prerequisite materials for phospholipid synthesis (Merrill et al., 1997; Schmelz et al., 1994). Radiolabeled ganglioside [3H]sphingosine-GM1 when injected intraperitoneally into mice was incorporated into hepatocyte phospholipids in the EPL form (Ogura et al., 1988).
Ether Phospholipids.
To date, there has been no research investigating whether dietary gangliosides can be used for synthesis of EPL in the intestine or influence EPL synthesis in neuronal tissues. EPL have an ester linkage at the sn-2 position, but have an ether linkage, either to an alkyl or alkenyl group, at the sn-1 position. EPL tend to be enriched in mammalian intestinal and neuronal cells (Paltauf, 1972). One type of EPL known as plasmalogens (a group of 1-O-alkenyl-2-acyl-glycero-phospholipids), accounts for about 75% of ethanolamine phosphoglycerides (EPG) in myelin of rat brain, 65% of EPG in human brain (Horrocks, 1972) and 12% of EPG in rat intestinal mucosa (Paltauf, 1972). High content of EPL may contribute to maintenance of cell integrity and function (Alonso et al., 1997; Bittman et al., 1984; Diomede et al., 1993; Honma et al., 1981; Mavromoustakos et al., 2001; Oishi et al., 1988; Paltauf, 1994; Principe et al., 1994; Seewald et al., 1990; and Zheng et al., 1990). EPL can affect membrane properties such as permeability (Bittman et al., 1984) and fluidity (Paltauf, 1994). EPL influence signal transduction to many metabolic pathways by protein kinase C (PKC) (Zheng et al., 1990), Na—K-ATPase (Oishi et al., 1988), inositol-lipid turnover (Seewald et al., 1990), and intracellular calcium (Alonso et al., 1997). EPL induce cell apoptosis (Alonso et al., 1997), cytotoxicity (Diomede et al., 1993; Honma et al., 1981), and antitumor activity (Mavromoustakos et al., 2001; Principe et al., 1994), which could have potential in anti-cancer applications. Selective cytotoxic effects of EPL is dependent on membrane cholesterol amount (Diomede et al., 1990). For example, HL60 cells with a high cholesterol content show lower uptake of EPL into membranes, resulting in decrease in membrane fluidity (Diomede et al., 1990) and higher rates of apoptosis (Diomede et al., 1993). Alkyl-lysophospholipids exhibit strong selective cytotoxicity in leukemia cells but not in normal bone marrow cells (Honma et al., 1981).
Gangliosides and EPL may perform similar functions. For example, both of these types of lipids localize in neuronal (Byrne et al., 1983; Svennerholm et al., 1989; and Horrocks 1972) and intestinal tissues (Forstner et al., 1973; Paltauf, 1972). Both gangliosides and EPL exhibit anti-cancer effects (Mavromoustakos et al., 2001; Principe et al., 1994; Schmelz et al., 2000) and contribute to cell differentiation (Ledeen et al., 1998; Honma et al., 1981) and apoptosis (Diomede et al., 1993; Malisan et al., 2002). Gangliosides and EPL are sensitive to membrane cholesterol content (Diomede et al., 1990; Blank et al., 1992).
In American diets daily intake of SPL (including gangliosides and sphingomyelin) is about 300 mg (Vesper et al., 1999) and daily intake of EPL is about 1 mg per gram of food (Berger et al., 2000). Neonates consume SPL and EPL from mothers milk (Diomede et al., 1991), but the metabolic interaction between dietary SPL and EPL is not known.
Cholesterol reduction in membranes causes increased EPL uptake (Diomede et al., 1990; Leikin et al., 1988) and increased activity of Δ-5 and Δ-6 desaturase enzymes (Clandinin et al., 1991). Dietary gangliosides may increase total membrane EPL content and accompanied with higher polyunsaturated fatty acid (PUFA) in subclasses of EPL. Sphingomyelin can be used as a control to compare bioavailability with gangliosides because sphingomyelin and gangliosides have the same ceramide molecule anchored in the cell membrane, but attached to a different head group. Using rats, the present data illustrated herein demonstrates that dietary ganglioside increases total content and composition of EPL containing PUFA in the developing intestine.
Microdomains.
Microdomains, generally called lipid rafts, caveolae, or glycosphingolipid-signaling domains, have been characterized as important domains for signal transduction and lipid (i.e. cholesterol) and protein trafficking (Anderson, 1998; Brown et al., 1998; Hakomori et al., 2000; and Simons et al. 1997). Microdomains are recently known as a site for the cellular entry of bacterial and viral pathogens (Fantini, 2000; Katagiri et al., 1999; and Bavari et al., 2002). For instance, the entry of filoviruses requires lipid rafts as the site of virus attack (Bavari et al., 2002). Cholera toxin entered the cell by endocytosis GM1 as the sorting motif necessary for retrograde trafficking into host cells and such trafficking depends on association with lipid rafts (Wolf et al., 2002).
Physiological and functional roles of microdomains are dependent on cholesterol and sphingolipids including gangliosides. Reduction of cholesterol inhibits pathogen entry by disrupting the structure of microdomains (Popik et al., 2002; Samuel et al., 2001) and impairs inflammatory signalling (Wolf et al., 2002; Triantafilou et al., 2002). Cholesterol upregulates the expression of caveolin, a marker of protein for caveolae (Fielding et al., 1997; Hailstones et al., 1998). Sphingolipid depletion inhibits the intracellular trafficking of GPI-anchored proteins and endocytosis via GPI-anchored proteins (Kasahara et al., 1999), suggesting that lipid-protein interaction directly modulates gene expression and cellular trafficking important for cell development and behaviour.
The neonatal intestine has permeable, endocytic and enzymatic transport systems for absorption of nutrients and immunoglobulins (Moxey et al., 1979; Wilson et al., 1991) but is susceptible to pathogen entry because of higher permeability than that of adults (Koldovsky 1994). High amount of gangliosides in mothers' milk during the neonatal period therefore act as a receptor for viral and bacterial toxins to protect entry of pathogens into enterocytes (Rueda et al., 1998). During development, membrane permeability gradually decreases (Koldovsky 1994) while peptidases and glycosidases become functionally active and enriched in microdomains (Danielsen et al., 1995). Many digestive/absorptive enzymes, such as alkaline phosphatase, aminopeptidase N and A, and sucrase-isomaltase are also increased in apical membrane microdomains (Stulnig et al., 2001). These results seem to suggest the importance of microdomains of intestinal apical membranes for nutrient uptake and metabolism.
Polyunsaturated fatty acids (20:5n-3 or 22:6n-3) can accumulate in microdomains and displace functional proteins by changing the lipid composition of the microdomain (Stulnig et al., 2001; Williams et al., 1999). This observation highlights the importance of dietary lipids in modulating physiological and biological properties of proteins in the microdomain. Little is known of how dietary gangliosides affect the lipid profile and protein components of microdomains during neonatal gut development.
Some previous studies have suggested that cholesterol depletion inhibits inflammatory signaling by disrupting microdomains structure (Wolf et al., 2002; Samuel et al., 2001; Triantafilou et al., 2002). However, it has not been evaluated whether diet-induced cholesterol reduction has any effect on decreasing cholesterol in the microdomain, disrupting microdomain structure and reducing pro-inflammatory mediators such as diglyceride (DG) and platelet activating factor (PAF). DG derived from phospholipids by phospholipase C, binds to protein kinase C (PKC) to phosphorylate targeted proteins, such as the epidermal growth factor receptor and DG resides in microdomains (Sciorra et al., 1999; Smart et al., 1995).
PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine, stimulates inflammatory cells such as leukocytes (Prescott et al., 1990) and activates phospholipase A2 (PLA2) in the intestinal tissue to release arachidonic acid (Okayasu et al., 1987). Meanwhile, increased lyso-PC by PLA2 is further used for PAF synthesis with an acetylcholine transferase. PAF binds its receptor to increase intracellular calcium and inositol triphosphate (IP3) production and PKC activation for inflammation (Flickinger et al., 1999). It is unknown if PAF also localizes in the microdomain. Since several studies reported that sphingomyelin (SM), a sphingolipid, has an inhibitory effect on PLA2 activity (Koumanov et al., 1997), it was of interest to determine if dietary ganglioside also decreases PAF synthesis either by increasing sphingolipids or by disrupting microdomains structure in developing intestine. Whether dietary ganglioside reduces DG content in the microdomain was also examined since sphingosine, a derivative of sphingolipids inhibits PKC signaling which is required a structural complex with DG.
Neonates consume SPL including gangliosides from mothers milk (Carlson 1985; Berger et al., 2000). Gangliosides are known to act as receptors for viruses and toxins (Laegreid et al., 1987; Rolsma et al., 1998), activators for T-cells (Ortaldo et al., 1996) and stimulators for Th-1 and Th-2 cytokine-secreting lymphocytes in neonates (Vazquez et al., 2001). Gangliosides are also one of the major lipid components in microdomains. It is not known if dietary ganglioside changes the lipid profile and structure of the intestinal microdomain and modulating inflammatory signalling mechanisms in the developing intestine.
Necrotizing enterocolitis is an Inflammatory Bowel Disease of neonates and remains the leading gastrointestinal emergency in premature infants. Since current treatments disrupt the natural microflora, are invasive and do not target the specific processes underlying development of necrotizing enterocolitis, it remains the leading cause of morbidity and mortality in neonatal intensive care units. Prematurity, hypoxia-ischemia, infection and formula feeding are established risk factors, and breastfeeding is protective.
It is desirable to find a compound, a class of compounds, or composition active in treating inflammation. It is also desirable to find such compounds or compositions that is naturally occurring in the food supply, so as to more easily meet with public acceptance.
Further, it is desirable to find a compound, a class of compounds, or composition active in treating inflammation. Advantageously, such compounds or compositions would be naturally occurring in the food supply, so as to more easily meet with public acceptance.
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Abbreviations used herein are as follows:
CPG: Choline phosphoglycerides; DG: diacylglycerol; E. Coli: Escherichia coli; EPG: Ethanolamine phosphoglycerides; EPL: Ether phospholipids; Gang-High: High concentration of ganglioside; Gang-Low: Low concentration of ganglioside; GD1b: II3 (NeuAc)2-GgOse4Cer; GD3: Ganglioside GD3: II3 (NeuAc)2-LacCer; GLC: Gas liquid chromatography; GG: gangliosides; GM1: Ganglioside GM1; II3 NeuAc-GgOse4Cer; GM2: Ganglioside GM2: II3 NeuAc-GgOse3Cer; GM3: Ganglioside GM3: II3 NeuAc-LacCer; LCPUFA: Long chain polyunsaturated fatty acids; LPC: lysophosphatidylcholine; LPE: lysophosphatidylethanolamine; MUFA: monounsaturated fatty acids; NANA: N-Acetyl neuraminic acid; PAT: platelet activating factor; PBS: Phosphate buffered saline solution; PC: phosphatidylcholine; PE: phosphatidyl ethanoloamine; PI: phosphatidylinositol; PKC: Protein kinase C; PL, phospholipids; PS: phosphatidylserine; PUFA: polyunsaturated fatty acids; SEM: Standard error of the mean; SFA: Saturated fatty acids; sIgA: Secretory immunoglobulin A; SM: sphingomyelin; SPL: Sphingolipids; TG: Triglyceride; and TLC: Thin layer chromatography. Additional abbreviations include: PL=phospholipid, ROS=reactive oxygen species, COX-2=cyclooxygenase-2, 5 LOX=5 lipoxygenase, nNOS=neuronal nitric oxide synthase, iNOS=inducible nitric oxide synthase. BNIP3=bcl-2 nineteen kilodalton interacting protein 3, GM-CSF=granulocyte macrophage-colony stimulating factor.